CN109562353B - Removal of endotoxemia-inducing molecules using a hemocompatible porous polymer bead sorbent - Google Patents

Abstract

The present invention relates to biocompatible polymer systems comprising at least one polymer having a plurality of pores, said polymer comprising polyols or zwitterionic groups designed to adsorb endotoxins and other inflammatory mediator molecules. The present invention is in the field of porous polymeric adsorbents, in the field of the wide reduction of endotoxins in blood and blood products that can cause endotoxemia, and in the field of the wide removal of endotoxins by perfusion or blood perfusion.

Description

Removal of endotoxemia inducing molecules using a hemocompatible porous polymer bead sorbent

RELATED APPLICATIONS

The present application claims the benefit of U.S. patent application No.62/341,676 filed 2016, 5, 26, the disclosure of which is incorporated herein in its entirety.

Technical Field

The disclosed invention relates to the field of porous polymeric sorbents (sorbents). The disclosed invention is also in the field of the broad reduction of endotoxins in blood and blood products that can cause endotoxemia. In addition, the disclosed invention is also in the field of the widespread removal of endotoxins by perfusion or blood perfusion.

Background

Gram-negative bacterial cell walls contain bound toxic substances called endotoxins or Lipopolysaccharides (LPS). Structurally, LPS is composed of three distinct regions: o-antigen, core and lipid a. The O-antigen is a repetitive glycan polymer comprising the hydrophilic outermost region of the molecule and the composition of LPS differs for each strain. The core links the O-antigen to lipid a, a biologically active phosphorylated glucosamine disaccharide containing multiple hydrophobic fatty acid tails. These fatty acid tails are responsible for anchoring LPS in the bacterial cell wall. The core of LPS and lipid a are highly conserved among different strains, lipid a being the main toxic component.

Endotoxin can enter the bloodstream through two major pathways, where intravenous doses as low as 1ng per kg body weight per hour can elicit an inflammatory response in humans. The first is local or systemic infection by exogenous gram-negative bacteria, and the second is translocation across the intestinal membrane by endogenous gram-negative bacteria or fragments thereof. Once in circulation, LPS can induce an inflammatory response by binding to lipopolysaccharide binding protein (LPB) to form an LPS-LPB complex, which subsequently elicits an immune system and histiocytic response. Long-term and up-regulated inflammatory responses may lead to sepsis or Systemic Inflammatory Response Syndrome (SIRS), both of which may progress to potentially fatal septic shock and Multiple Organ Dysfunction Syndrome (MODS).

Endotoxins are also associated with a myriad of syndromes and diseases. These include complications from trauma, burns and invasive surgery, as well as organ-specific diseases such as liver disease, renal dialysis complications and autoimmune diseases.

Currently, there are many commercial endotoxin adsorbents. A number of available products are based on Polymyxin B (PMB) immobilized on agarose gels, including Detoxi-Gel Endotoxin Removinggel (Thermo Fisher Scientific), AffiPrep Polymyxin Matrix (BioRad), Polymyxin B agarose (Sigma-Aldrich) and Endotoxin Affi besent (bioWORLD). Toraymyxin (Toray Medical Co.) is a PMB-based extracorporeal device designed for selective blood endotoxin purification by direct blood perfusion and approved as a therapeutic device by the japanese health insurance system. Polymyxin B is characterized by a heptapeptide ring, a tripeptide group and a fatty acid tail, and is an antibiotic primarily used to resist gram-negative infections. The positively charged diaminobutyric acid group of PMB interacts with the negatively charged phosphate group of LPS, resulting in an interaction between the N-terminal fatty acyl chain of PMB and the lipid a fatty acyl tail, thereby forming a very stable PMB-LPS complex. (Harm, Stephan, Dieter Falkenhagen, and Jens Hartmann. "endo-absorbers in Extracorporeal Blood Purification: Do the y Fulfill Expectations.

Anion exchange resins can also be used for LPS removal using the negatively charged groups of LPS. Diethylaminoethyl-cellulose (DEAE-cellulose) resin is positively charged due to tertiary amine functionality, and Bentsch et al have reported binding LPS in plasma by DEAE-cellulose adsorbents at physiological pH with high affinity and capacity. However, the decrease in endotoxin levels was accompanied by a transient but reversible increase in prothrombin time. (Bentsch S, Boos KS, Nagel D, Seidel D, Inthom D. expression plasmid reaction for the removal of endoxin in tissues with syndrome: clinical results of a pilot. shock. 2005; 23 (6): 494-. Alteco LPS Adsorber (Alteco Medical AB) consists of a polyethylene plate with immobilized specific cationic peptide HAE 27, which cationic peptide HAE 27 selectively binds and adsorbs LPS. In addition, the Endotrap (Profos AG) adsorbent consists of bacteriophage proteins immobilized on Sepharose beads, wherein the bacteriophage proteins have a high affinity for LPS molecules.

The adsorption capacity of many commercial endotoxin adsorbents was evaluated in the study of Harm et al. Adsorbents tested included Toray LPS adsorbent, Toray PMX-20R, Alteco LPS adsorbent, Ethylaminoethyl-Sepharose (DEAE-Sepharose), Polymyxin B-Agarose and Endotrap red, and mobile phases used in the study included buffer solution, protein solution, serum, heparinized plasma and whole blood. Only Alteco LPS Adsorber and Toraymyxin PMX-20R were hemocompatible, and therefore only these adsorbents were tested in whole blood. These two adsorbents are also the only two of the aforementioned products designed for blood perfusion applications. In a batch adsorption test using 10% adsorbent in 100ng FITC-LPS/mL, DEAE-Sepharose adsorption capacity was optimized compared to other test materials, reducing LPS levels to 18 + -8.5% of control in 10mM PBS buffer, and to 37 + -4% of control in 4% (w/v) Human Serum Albumin (HSA) solution. Toraymyxin is the only other adsorbent that was able to reduce activity by less than 70% and 95% in PBS and HSA solutions, respectively, resulting in a reduction to 21 + -2% in PBS and 87 + -6% in HSA solution. Batch tests in serum and heparinized plasma were performed using 10% adsorbent in 5ng LPS/mL spiked serum or plasma. DEAE-Sepharose is most effective for removing LPS from serum, reducing the value to 28 ± 0.8% of the control; however, since DEAE-Sepharose's heparin-binding ability causes plasma coagulation, it cannot be tested in heparinized plasma. PMB-sepharose was the second most efficient, reducing LPS levels to 36 ± 3.6% and 64 ± 6.8% of control in serum and heparinized plasma, respectively. Toraymyxin is the only other adsorbent that was able to reduce levels below 75% of control, reducing LAL activity to 41 + -3.5% and 65 + -4.5% of control in serum and heparinized plasma, respectively. Toray reduces activity to 60 + -14% of control in a batch test using 5% (w/v) adsorbent and a LPS concentration of 3ng/mL in whole Blood, whereas Alteco LPS adsorbent cannot reduce activity by less than 90% (Harm, Stephan, Dieter Falkenhagen, and Jens Hartmann, "endo adsorption in extracellular Blood Purification: Do the y functional assays.

For blood perfusion applications, a problem with using immobilized PMB on a polymer support is that non-covalently bound PMB may leach from the support into the recirculating blood. Polymyxin B has been shown to cause Neurotoxicity in some patients receiving intravenous therapy (Weinstein, L, TL Doan, and MA Smith. "Neurooxicity in tissues treated with intraviral polymyxin B: Two cases ports." Am JHault Syst Pharm 2009Feb 15; 66 (4): 345-7). In addition, PMB has been shown to induce nephrotoxicity in some patients receiving intravenous therapy (Sobieszczyk, ME, et al, "Combination therapy with a polymyxin B for the treatment of multi-drug Gram-negative resistance therapy infections," J antibacterial therapy.2004 Aug; 54 (2): 566-9). In the study by Harm et al (see above), non-covalently bound PMB from Toray fibers and PMB-agarose beads was removed by a series of washing steps and quantified using HPLC. The fibers or beads were incubated 10 times in physiological saline solution and then 5 times in 0.1N HCl solution. After a fifth 0.1N HCl wash step, 42. + -.12 ng PMB/mL was found from the Toray fiber. After the fourth 0.1N HCl wash step, 27. + -.6 ng PMB/mL was found from PMB-agarose beads.

As previously mentioned, endotoxins are components of the cell wall of gram-negative bacteria. Gram-negative bacteria are commonly used to produce recombinant proteins, and many techniques for extracting the desired recombinant protein from bacterial cells also release lipopolysaccharides. The purification of recombinant proteins using ion exchange columns is not always completely successful, since LPS tends to form complexes with proteins by specific or non-specific interactions, and the entire complex becomes immobilized on the column. Ropp et al developed a technique for separating LPS from protein-LPS complexes using alkanediols, leaving the protein immobilized on an ion exchange column (PCT International application (2005), WO 2005003152A 120050113). Alkanediols were chosen because of reduced toxicity and flammability compared to other agents that achieved similar separations.

In addition, alkanediols exhibit broad antimicrobial activity and have been used as moisturizing antimicrobials in cosmetics. In the optimized structure Of dimers and trimers Of 1, 2-hexanediol and (S) -3- (hexyloxy) propane-1, 2-diol in water, the amphiphilicity Of the alkanediols increases as the two hydroxyl groups become closer and the aliphatic chain becomes longer, and therefore, it is likely to penetrate more easily into the membrane bilayer Of microbial cells (Yoo IK, JII Kim, YK kang. "structural precursors and antimicrobial activities Of alkamines." comparative and therapeutic Chemistry 2015, Vol. 1064, 15-24.).

Lipoteichoic acid (LTA) is a major component of the cell wall of gram-positive bacteria and has many of the same pathogenic properties as LPS. LTA is anchored in the cell wall by glycolipids, which have a similar effect to lipid A in LPS (Morath S, et al, "Structure/function relationships of lipid acids. JEndotoxin Res.2005; 11 (6): 348-56.). If released from the cell wall, it may bind non-specifically to membrane phospholipids of the target cell or specifically to toll-like receptors of the target cell and activate the complement cascade or cause the release of active substances and cytokines, which may serve to augment cell damage. LTA plays an important Role in infections caused by gram-positive bacteria and has been shown in animal studies to cause cascades that, in addition to meningitis, encephalomyelitis and arthritis, lead to multiple organ failure and septic shock (Ginsburg I. "Role of sexual acid in infection and inflammation." Lancet Infect Dis.2002 Mar; 2 (3): 171-9).

Disclosure of Invention

The novel sorbent materials described herein offer advantages over the prior art in that endotoxin levels in biological fluids are reduced without potential leaching of harmful substances, resulting in a safe and effective process. This sorbent material differs from other prior art materials due to the net neutral charge of the functional groups covalently attached to the polymer matrix. LPS can be retained by the new sorbent material through tortuous pathways, adsorption and pore capture. The resins comprising polyol groups and zwitterionic groups covalently bound to a poly (styrene-co-divinylbenzene) backbone can be synthesized using a variety of approaches. For blood perfusion applications, the polymer is required to be hemocompatible. Using the unactivated partial thromboplastin time (uttt) assay as a measure of thrombus formation, the polymers described herein showed minimal activation, indicating plasma-like interactions. In addition, the sorbent is capable of removing cytokines and inflammatory protein moieties simultaneously with endotoxin removal, and has the potential to exhibit antimicrobial activity. Removal of endotoxin or cytokines from endotoxemia patients may be an inadequate treatment because the remaining endotoxin will cause more cytokine production and the remaining cytokines may still lead to sepsis. By eliminating the root cause of infection and subsequent excessive inflammatory response, this new sorbent offers advantages over prior art specifically designed for endotoxin removal.

In some aspects, the present invention relates to a biocompatible polymer system comprising at least one polymer comprising a polyol or zwitterionic functional group; the polymer system is capable of adsorbing endotoxins. Preferred polymers are also capable of adsorbing a variety of toxins and inflammatory mediators having a molecular weight of less than about 0.5kDa to about 1,000kDa (or in some embodiments, about 1kDa to about 1,000 kDa). Some preferred polymers are hemocompatible. Certain preferred polymer systems have a spherical bead geometry.

Some preferred polymers are also capable of adsorbing one or more of gram negative bacteria, gram negative bacterial fragments, and gram negative bacterial components. Gram-negative bacterial components include, but are not limited to, Lipopolysaccharide (LPS). Other preferred polymers are also capable of adsorbing one or more of gram positive bacteria, gram positive bacterial fragments and gram positive bacterial components. Gram positive bacterial components include, but are not limited to lipoteichoic acid (LTA). In some embodiments, the toxin and inflammatory mediator comprise one or more of: cytokines, pathogen associated molecular pattern molecules (PAMPs), damage associated molecular pattern molecules (DAMPs), superantigens, monokines, chemokines, interferons, proteases, enzymes, peptides including bradykinin, soluble CD40 ligands, bioactive lipids, oxidized lipids, acellular hemoglobin, acellular myoglobin, growth factors, glycoproteins, prions, toxins, bacterial and viral toxins, drugs, vasoactive substances, foreign antigens, and antibodies.

The polymer may be prepared by any method known in the art to produce a suitable porous polymer. In some preferred embodiments, the polymer is prepared using suspension polymerization. In other embodiments, the polymer is prepared by emulsion polymerization, bulk polymerization, or precipitation polymerization.

The polymer is in the form of a solid support. In some preferred embodiments, the solid support is a bead. In other embodiments, the solid support is a fiber, monolithic column (monolithic column), or membrane.

Some polymer systems have a polymer pore structure, which

To

The total volume of pore sizes in the range is greater than 0.1cc/g and less than 5.0cc/g dry polymer, while other polymer systems are non-porous. Other embodiments have a polymeric pore structure, which

To is that

The total volume of pore sizes in the range is greater than 0.1cc/g and less than 3.0cc/g dry polymer, while other polymer systems are non-porous。

In certain embodiments, the polymer is in the form of hypercrosslinked or macroreticular porous polymer beads comprising polyol groups. In certain other embodiments, the polymer is in the form of a hypercrosslinked or macroreticular porous polymer bead comprising zwitterionic groups. In some preferred embodiments, the polymer is in the form of hypercrosslinked or macroreticular porous polymer beads comprising diol groups.

In certain embodiments, the polymer is in the form of non-porous polymer beads comprising polyol groups. In certain other embodiments, the polymer is in the form of non-porous polymer beads comprising zwitterionic groups. In some preferred embodiments, the polymer is in the form of non-porous polymer beads comprising diol groups.

In some embodiments, the polymeric beads comprise polyol groups. The polymer beads comprising polyol groups may be produced by a ring-opening reaction of a preformed polymer comprising epoxy groups. In some preferred embodiments, the polyol groups are diol groups.

In other embodiments, polymer beads comprising polyol groups may be produced by an ester hydrolysis reaction of a preformed polymer comprising residual acetate groups. In some preferred embodiments, the polyol groups are diol groups.

In other embodiments, the polymeric beads comprise zwitterionic functional groups. The polymeric beads containing zwitterionic functional groups can be produced by free radical reaction in the presence of zwitterionic monomers containing readily polymerizable double bonds.

Some polymer systems are constructed from polymerizable vinyl monomers containing epoxy groups, which are copolymerized in the presence of a cross-linking agent, a hemocompatible monomer, a monomer, and a suitable porogen to produce a porous polymer containing epoxy functional groups. These epoxides are then converted to polyols by a ring-opening reaction in the presence of a base. In some preferred systems, the epoxide is converted to a diol.

Other polymer systems are constructed from polymerizable vinyl monomers containing acetate groups, which are copolymerized in the presence of a cross-linking agent, a hemocompatible monomer, a monomer, and a suitable porogen to produce porous polymers containing acetate groups. These acetate groups are converted to polyols by ester hydrolysis in the presence of a base. In some preferred embodiments, the polyol groups are diol groups.

Some polymer systems are constructed from polymerizable vinyl monomers containing epoxy groups that are copolymerized in the presence of a cross-linking agent, a hemocompatible monomer, and a monomer to produce a non-porous polymer containing epoxy functionality. These epoxides are then converted to polyols by a ring-opening reaction in the presence of a base. In some preferred systems, the epoxide is converted to a diol.

Other polymer systems are constructed from polymerizable vinyl monomers containing acetate groups that are copolymerized in the presence of a crosslinking agent, a hemocompatible monomer, and a monomer to produce a non-porous polymer containing acetate. These acetate groups are converted to polyols by ester hydrolysis in the presence of a base. In some preferred embodiments, the polyol groups are diol groups.

Certain polymers are formed and subsequently modified to be biocompatible. Some modifications include forming a biocompatible surface coating or layer. Another aspect relates to a device for removing endotoxin from a physiological fluid comprising a biocompatible polymer system as described herein. Another aspect relates to a device for also removing a plurality of protein-based toxins of less than 0.5kDa to 1,000kDa from a physiological fluid, comprising a biocompatible polymer system as described herein.

Other aspects relate to devices for also removing one or more of gram-negative bacteria, gram-negative bacterial fragments, and gram-negative bacterial components from a physiological fluid, comprising the biocompatible polymer systems described herein. Further aspects relate to a device for also removing one or more of gram positive bacteria, gram positive bacterial fragments and gram positive bacterial components from a physiological fluid comprising a biocompatible polymer system as described herein.

Another aspect relates to a device for removing endotoxin from a non-physiological fluid comprising a biocompatible polymer system as described herein. Another aspect relates to a device for also removing a plurality of protein-based toxins of less than 0.5kDa to 1,000kDa from a non-physiological fluid, comprising a biocompatible polymer system as described herein.

Other aspects relate to a device for also removing one or more of gram-negative bacteria, gram-negative bacterial fragments, and gram-negative bacterial components from a non-physiological fluid, comprising a biocompatible polymer system described herein. A further aspect relates to a device for also removing one or more of gram positive bacteria, gram positive bacterial fragments and gram positive bacterial components from a non-physiological fluid comprising a biocompatible polymer system as described herein.

Further aspects include perfusion methods comprising a single pass of a physiological fluid or multiple passes through a device comprising a biocompatible polymer system described herein with the aid of a suitable extracorporeal circuit.

Further aspects relate to uses thereof for enteral or rectal administration of the polymers described herein.

In some aspects, the present invention relates to a non-biocompatible polymer system comprising at least one polymer comprising a polyol or a zwitterionic functional group; the polymer system is capable of adsorbing endotoxins from a physiological fluid, a laboratory or manufacturing fluid or a water system of one or more of a medical facility, a home healthcare application, a pharmaceutical facility, a biotechnology facility, a biological manufacturing process, a cell culture manufacturing process, and a laboratory. Preferred polymers are also capable of adsorbing one or more of a variety of toxins, bacteria, bacterial debris, and bacterial components.

Brief Description of Drawings

The accompanying drawings, which are included to provide a further understanding of the disclosure, are incorporated in and constitute a part of this specification, illustrate aspects of the disclosure and together with the detailed description serve to explain the principles of the disclosure. No attempt is made to show structural details of the disclosure in more detail than is necessary for a fundamental understanding of the disclosure and the various ways in which it may be practiced. In the drawings:

fig. 1, 2, 3 and 4 show log differential pore volume plots for the modified polymers.

Figure 5 shows endotoxin removal data from a dynamic model in human plasma for modified polymers CY15129, CY15154 and CY16000, expressed as a percentage determined by the amount of endotoxin remaining after 120 minutes compared to the pre-circulating concentration.

Figure 6 shows endotoxin removal data from a dynamic model in human plasma for polymer CY15154 and its unmodified precursor CY15077, expressed as a percentage determined by the amount of endotoxin remaining after 120 minutes compared to the pre-circulation concentration.

Figure 7 shows cytokine removal data from a dynamic model in whole blood, expressed as a percentage determined by the amount of cytokine remaining at a particular time point compared to the pre-circulation concentration.

Detailed description of exemplary embodiments

As required, detailed embodiments of the present invention are disclosed herein; it is to be understood that the disclosed embodiments are merely exemplary of the invention, which can be embodied in various forms. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for teaching one skilled in the art to employ the present invention. The following specific examples will allow the invention to be better understood. However, they are given by way of guidance only and are not meant to be limiting in any way.

The present invention may be understood more readily by reference to the following detailed description and the accompanying drawings, which form a part hereof, and the embodiments. It is to be understood that this invention is not limited to the specific materials, devices, methods, applications, conditions or parameters described and/or illustrated herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed invention. The term "plurality" as used herein means more than one. When a range of values is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. All ranges are inclusive and combinable.

It is to be understood that certain features of the invention, which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination. In addition, reference to values stated in ranges includes each and every value within that range, as well as combinations of values.

The following definitions are intended to aid in understanding the invention:

the term "biocompatible" is defined to mean that the sorbent is capable of being contacted with a physiological fluid, living tissue, or organism without producing unacceptable clinical changes during contact of the sorbent with the physiological fluid, living tissue, or organism.

The term "hemocompatibility" is defined as the condition that results in a clinically acceptable physiological change when the biocompatible material is contacted with whole blood or plasma.

As used herein, the term "physiological fluid" is a body-derived fluid that may include, but is not limited to, nasopharyngeal, oral, esophageal, gastric, pancreatic, liver, thoracic, pericardial, peritoneal, intestinal, prostate, seminal, vaginal secretions, as well as tears, saliva, lung or bronchial secretions, mucus, bile, blood, lymph, plasma, serum, synovial fluid, cerebrospinal fluid, urine, and interstitial, intracellular and extracellular fluids, such as fluids exuded from burns or wounds.

As used herein, the term "laboratory or manufacturing fluid" is defined as a liquid for life science applications, including, but not limited to, tissue and cell culture media and additives, chemical or biological assay media, sample preparation buffers, biological manufacturing media, growth media, and bioreactor media

As used herein, the term "sorbent" includes adsorbents and absorbents.

For the purposes of the present invention, the term "adsorption" is defined as "uptake and binding by absorption and adsorption".

For the purposes of the present invention, the term "perfusion" is defined as the single passage of a physiological fluid through a device comprising a porous polymeric adsorbent, or by means of a suitable extracorporeal circuit, to remove toxic molecules from the fluid.

The term "blood perfusion" is a special case of perfusion, in which the physiological fluid is blood.

The term "dispersing agent" or "dispersing agent" is defined as a substance that imparts a stabilizing effect to a finely dispersed array of immiscible liquid droplets suspended in a fluidized medium.

The term "heparin mimetic polymer" refers to any polymer that has the same anticoagulant and/or antithrombotic properties as heparin.

The term "macroreticular synthesis" is defined as the polymerization of monomers into polymers in the presence of an inert precipitating agent, which forces the growing polymer molecules away from the monomer liquid at a specific molecular size dictated by phase equilibrium, such that solid nano-sized spherical or near-spherical symmetric microgel particles pack together to form beads with open-celled physical pores [ U.S. patent 4,297,220, Meitzner and Oline, October 27, 1981; l. Albright, Reactive Polymers, 4, 155-174(1986) ].

The term "hypercrosslinked" describes a polymer in which a single repeat unit has more than two linkages. Hypercrosslinked polymers are prepared by crosslinking swollen or dissolved polymer chains with a large number of rigid bridging spacers, rather than copolymerization of monomers. Crosslinking agents may include bis (chloromethyl) ethers of aromatic hydrocarbons, methylal, monochlorodimethyl ethers and other difunctional compounds which react with polymers in the presence of Friedel-Crafts catalysts [ tsyuroupa, m.p., z.k.blinnikova, n.a.prosurina, a.v.pastukhov, l.a.pavlova, and v.a.davankov. The First Nanoporus Polymeric Material, "Nanotechnologies in Russia 4 (2009): 665-75.].

Some preferred polymers comprise residues from, or contain residues from, one or more monomers, or mixtures thereof, selected from acrylonitrile, allyl glycidyl ether, butyl acrylate, butyl methacrylate, cetyl acrylate, cetyl methacrylate, 3, 4-dihydroxy-1-butene, dipentaerythritol diacrylate, dipentaerythritol dimethacrylate, dipentaerythritol tetraacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol triacrylate, dipentaerythritol trimethacrylate, divinylbenzene, divinylformamide, divinylnaphthalene, divinylsulfone, 3, 4-epoxy-1-butene, 1, 2-epoxy-9-decene, 1, 2-epoxy-5-hexene, di-and tri-vinyl methacrylates, and mixtures thereof, Ethyl acrylate, ethyl methacrylate, ethylstyrene, ethylvinylbenzene, glycidyl methacrylate, methyl acrylate, methyl methacrylate, octyl acrylate, octyl methacrylate, pentaerythritol diacrylate, pentaerythritol dimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, pentaerythritol triacrylate, pentaerythritol trimethacrylate, styrene, trimethylolpropane diacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, trivinylbenzene, trivinylcyclohexane, vinyl acetate, vinylbenzyl alcohol, 4-vinyl-1-cyclohexene 1, 2-epoxide, vinylformamide, vinylnaphthalene, 2-vinyloxirane and vinyltoluene.

Some embodiments of the invention use organic solvents and/or polymeric porogens as porogens or porogens, and the resulting phase separation caused during polymerization produces porous polymers. Some preferred porogens are selected from the following or mixtures comprising any combination of the following: benzyl alcohol, cyclohexane, cyclohexanol, cyclohexanone, decane, dibutyl phthalate, di-2-ethylhexyl phosphate, ethyl acetate, 2-ethyl-1-hexanoic acid, 2-ethyl-1-hexanol, n-heptane, n-hexane, isoamyl acetate, isoamyl alcohol, n-octane, pentanol, poly (propylene glycol), polystyrene, poly (styrene-co-methyl methacrylate), tetralin (tetraline), toluene, tri-n-butyl phosphate, 1, 2, 3-trichloropropane, 2, 4-trimethylpentane, and xylene.

In another embodiment, the dispersant is selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, poly (diethylaminoethyl acrylate), poly (diethylaminoethyl methacrylate), poly (dimethylaminoethyl acrylate), poly (dimethylaminoethyl methacrylate), poly (hydroxyethyl acrylate), poly (hydroxyethyl methacrylate), poly (hydroxypropyl acrylate), poly (hydroxypropyl methacrylate), poly (vinyl alcohol), poly (acrylic acid) salts, poly (methacrylic acid) salts, and mixtures thereof.

Preferred sorbents are biocompatible. In another embodiment, the polymer is biocompatible. In another embodiment, the polymer is hemocompatible. In yet another embodiment, the biocompatible polymer is hemocompatible. In yet another embodiment, the geometry of the polymer is spherical beads.

In another embodiment, the biocompatible polymer comprises poly (N-vinylpyrrolidone).

In another embodiment, the biocompatible polymer comprises a 1, 2-diol. In another embodiment, the biocompatible polymer comprises a 1, 3-diol.

In another embodiment, the biocompatible polymer comprises a heparin mimetic polymer.

A coating/dispersant on a poly (styrene-co-divinylbenzene) resin will provide the material with improved biocompatibility.

In yet another embodiment, a set of cross-linking agents consisting of: dipentaerythritol diacrylate, dipentaerythritol dimethacrylate, dipentaerythritol tetraacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol triacrylate, dipentaerythritol trimethacrylate, divinylbenzene, divinylformamide, divinylnaphthalene, divinylsulfone, pentaerythritol diacrylate, pentaerythritol dimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, pentaerythritol triacrylate, pentaerythritol trimethacrylate, trimethylolpropane diacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, trivinylbenzene, trivinylcyclohexane, and mixtures thereof.

In some embodiments, the polymer is a polymer comprising at least one crosslinker and at least one dispersant. The dispersant may be biocompatible. The dispersant may be selected from chemicals, compounds or materials, such as hydroxyethyl cellulose, hydroxypropyl cellulose, poly (diethylaminoethyl acrylate), poly (diethylaminoethyl methacrylate), poly (dimethylaminoethyl acrylate), poly (dimethylaminoethyl methacrylate), poly (hydroxyethyl acrylate), poly (hydroxyethyl methacrylate), poly (hydroxypropyl acrylate), poly (hydroxypropyl methacrylate), poly (vinyl alcohol), poly (acrylic acid) salts, poly (methacrylic acid) salts, and mixtures thereof; the crosslinking agent is selected from the group consisting of dipentaerythritol diacrylate, dipentaerythritol dimethacrylate, dipentaerythritol tetraacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol triacrylate, dipentaerythritol trimethacrylate, divinylbenzene, divinylformamide, divinylnaphthalene, divinylsulfone, pentaerythritol diacrylate, pentaerythritol dimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, pentaerythritol triacrylate, pentaerythritol trimethacrylate, trimethylolpropane diacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, trivinylbenzene, trivinylcyclohexane, and mixtures thereof. Preferably, the polymer occurs while the coating is formed, wherein the dispersant is chemically bound or entangled on the surface of the polymer.

In another embodiment, the biocompatible polymer coating is selected from the group consisting of poly (diethylaminoethyl methacrylate), poly (dimethylaminoethyl methacrylate), poly (hydroxyethyl acrylate), poly (hydroxyethyl methacrylate), poly (hydroxypropyl acrylate), poly (hydroxypropyl methacrylate), poly (N-vinyl pyrrolidone), poly (vinyl alcohol), poly (acrylic acid) salts, poly (methacrylic acid) salts, and mixtures thereof.

In another embodiment, the biocompatible oligomer coating is selected from the group consisting of poly (diethylaminoethyl methacrylate), poly (dimethylaminoethyl methacrylate), poly (hydroxyethyl acrylate), poly (hydroxyethyl methacrylate), poly (hydroxypropyl acrylate), poly (hydroxypropyl methacrylate), poly (N-vinyl pyrrolidone), poly (vinyl alcohol), poly (acrylic acid) salts, poly (methacrylic acid) salts, and mixtures thereof.

Some of the biocompatible sorbent compositions of the present invention comprise a plurality of pores. The biocompatible sorbent is designed to adsorb a variety of toxins ranging from less than 0.5kD to 1,000 kDa. While not intending to be bound by theory, it is believed that the sorbent functions by sequestering molecules of a predetermined molecular weight within the pores. As the pore size of the polymer increases, the size of molecules that can be adsorbed by the polymer will increase. Conversely, as pore size increases beyond the optimal pore size for adsorption of a given molecule, adsorption of the protein may or will decrease.

In certain methods, the solid form is porous. Some solid forms are characterized by having a pore structure in which

To

The total volume of pore sizes in the range is greater than 0.1cc/g and less than 5.0cc/g dry polymer.

In other methods, the solid form is non-porous.

In certain embodiments, the polymer may be prepared in the form of beads having a diameter of 0.1 micron to 2 centimeters. Some polymers are in the form of powders, beads, or other regularly or irregularly shaped particles.

In some embodiments, the plurality of solid forms comprises particles having a diameter of 0.1 microns to 2 centimeters.

In some methods, the undesirable molecules include endotoxins, gram negative bacteria, gram negative bacterial fragments, gram negative bacterial components, gram positive bacteria, gram positive bacterial fragments, and gram positive bacterial components, as well as inflammatory mediators and stimuli, including cytokines, pathogen-associated molecular pattern molecules (PAMPs), damage-associated molecular pattern molecules (DAMPs), superantigens, monokines, chemokines, interferons, proteases, enzymes, peptides including bradykinin, soluble CD40 ligand, bioactive lipids, oxidized lipids, acellular hemoglobin, acellular myoglobin, growth factors, glycoproteins, prions, toxins, bacterial and viral toxins, drugs, vasoactive substances, foreign antigens, and antibodies.

In some embodiments, the sorbent comprises a crosslinked polymeric material obtained from the reaction of a crosslinker with one or more of the following polymerizable monomers, followed by epoxidation and ring opening to form a polyol: acrylonitrile, allyl glycidyl ether, butyl acrylate, butyl methacrylate, hexadecyl acrylate, hexadecyl methacrylate, 3, 4-dihydroxy-1-butene, dipentaerythritol diacrylate, dipentaerythritol dimethacrylate, dipentaerythritol tetraacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol triacrylate, dipentaerythritol trimethacrylate, divinylbenzene, divinylformamide, divinylnaphthalene, divinylsulfone, 3, 4-epoxy-1-butene, 1, 2-epoxy-9-decene, 1, 2-epoxy-5-hexene, ethyl acrylate, ethyl methacrylate, ethylstyrene, ethylvinylbenzene, glycidyl methacrylate, methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, ethyl acrylate, ethyl methacrylate, ethyl acrylate, ethyl, Methyl methacrylate, octyl acrylate, octyl methacrylate, pentaerythritol diacrylate, pentaerythritol dimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, pentaerythritol triacrylate, pentaerythritol trimethacrylate, styrene, trimethylolpropane diacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, trivinylbenzene, trivinylcyclohexane, vinyl acetate, vinylbenzyl alcohol, 4-vinyl-1-cyclohexene 1, 2-epoxide, vinylformamide, vinylnaphthalene, 2-vinyloxirane and vinyltoluene. In some preferred sorbents, the polyol formed is a diol.

In another embodiment, the polymeric sorbent is prepared from the reaction of a crosslinker with vinyl acetate, followed by modification to form beads containing polyol groups. The reaction may be a copolymerization reaction, or a one-pot reaction, in which vinyl acetate is added once the initial polymerization is near completion, and a second free radical polymerization is initiated with unused initiator to add vinyl acetate groups to the surface of the polymer beads. Subsequent modifications to the vinyl acetate-containing polymer include the following in order: hydrolysis to convert acetate groups to hydroxyl groups, reaction with epichlorohydrin (epichlorohydrin) to form polymer beads containing epoxide groups, and ring opening to convert epoxide groups to polyol groups. In some preferred embodiments, the polyol is a diol.

Some embodiments of the invention involve direct synthesis of epoxy-containing polymer beads, followed by ring opening of the epoxy groups to form a polyol. One or more of the following polymerizable vinyl monomers containing epoxy groups can be polymerized in the presence of a crosslinking agent and monomer to produce polymer beads containing the functional groups described above: allyl glycidyl ether, 3, 4-dihydroxy-1-butene, 3, 4-epoxy-1-butene, 1, 2-epoxy-9-decene, 1, 2-epoxy-5-hexene, glycidyl methacrylate, 4-vinyl-1-cyclohexene 1, 2-epoxide and 2-vinyloxirane. The epoxy group-containing vinyl monomer can also be copolymerized with a hemocompatible monomer (NVP.2-HEMA, etc.) to produce a hemocompatible bead containing epoxy groups. In some preferred embodiments, the polyol is a diol.

Other embodiments consist of hypercrosslinked polymer sorbents containing polyol groups on the surface of the beads. This may be by way of free radicals or S_NType 2 chemistry. The chemical modification of the surface of the sorbent beads (i.e., as in the case of the above-described modifications) is facilitated by the remarkable properties of hypercrosslinked polystyrene; that is, the reactive functional groups of the polymer are predominantly located on their surface. HypercrosslinkingPolystyrene is generally prepared by crosslinking polystyrene chains with a large number of difunctional compounds, in particular compounds bearing two reactive chloromethyl groups. The latter alkylates the two phenyl groups of adjacent polystyrene chains according to the Friedel-Crafts reaction in a two-step reaction, with the evolution (evolution) of two HCl molecules and the formation of cross-bridges. During the crosslinking reaction, the three-dimensional network formed acquires rigidity. This property gradually reduces the rate of the second step of the crosslinking reaction, as the mobility of the second side-chain functional group of the initial crosslinking reagent decreases making it increasingly difficult to add a suitable second partner for the alkylation reaction. This is especially a feature of the second functional group which happens to be exposed on the bead surface. Thus, the largest portion, if not most of the groups, of unreacted chloromethyl side groups in the final hypercrosslinked polymer are located on the surface of the beads (or on the surface of the wells). This allows the surface of the polymer beads to be modified primarily by including the aforementioned chloromethyl groups in a variety of chemical reactions that allow attachment of biocompatible and hemocompatible monomers, and/or cross-linkers or low molecular weight oligomers. Subsequent introduction of hydroxyl groups followed by reaction with epichlorohydrin results in a polymeric sorbent containing epoxy groups on the bead surface. These epoxy groups can then be ring opened to form polyol groups. In some preferred embodiments, the polyol is a diol.

In other embodiments, hypercrosslinked polystyrene containing pendant unreacted chloromethyl groups is directly modified in the presence of one or more of the following reagents to form sorbent polymer beads containing polyol on the bead surface (or pore surface): (±) -3-amino-1, 2-propanediol, glycerol, and other polyols. In some preferred embodiments, the polyol is a diol.

In other embodiments, the surface coating biocompatibility and hemocompatibility agent poly (vinyl alcohol) also serves as a polyol functionality.

In other embodiments, the sorbent comprises a crosslinked polymeric material obtained from the reaction of a crosslinker with one or more of the following polymerizable monomers, followed by reaction with a polymerizable zwitterionic monomer in the presence of a free radical initiator: acrylonitrile, allyl glycidyl ether, butyl acrylate, butyl methacrylate, hexadecyl acrylate, hexadecyl methacrylate, 3, 4-dihydroxy-1-butene, dipentaerythritol diacrylate, dipentaerythritol dimethacrylate, dipentaerythritol tetraacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol triacrylate, dipentaerythritol trimethacrylate, divinylbenzene, divinylformamide, divinylnaphthalene, divinylsulfone, 3, 4-epoxy-1-butene, 1, 2-epoxy-9-decene, 1, 2-epoxy-5-hexene, ethyl acrylate, ethyl methacrylate, ethylstyrene, ethylvinylbenzene, glycidyl methacrylate, methyl acrylate, ethyl methacrylate, ethyl acrylate, and the like, Methyl methacrylate, octyl acrylate, octyl methacrylate, pentaerythritol diacrylate, pentaerythritol dimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, pentaerythritol triacrylate, pentaerythritol trimethacrylate, styrene, trimethylolpropane diacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, trivinylbenzene, trivinylcyclohexane, vinyl acetate, vinylbenzyl alcohol, 4-vinyl-1-cyclohexene 1, 2-epoxide, vinylformamide, vinylnaphthalene, 2-vinyloxirane and vinyltoluene. The polymerizable zwitterionic monomers include one or more of: 2-acrylamido-2-methyl-1-propanesulfonic acid sodium salt, [3- (acryloylamino) propyl ] -trimethylammonium chloride, 3- [ [2- (acryloyloxy) ethyl) ] -dimethylammonium ] -propionate, [2- (acryloyloxy) ethyl ] -dimethyl- (3-sulfopropyl) -ammonium hydroxide, 2-acryloyloxyethyl phosphorylcholine, [3- (methacryloylamino) propyl ] -trimethylammonium chloride, 3- [ [2- (methacryloyloxy) ethyl ] -dimethylammonium ] -propionate, [2- (methacryloyloxy) ethyl ] -dimethyl- (3-sulfopropyl) -ammonium hydroxide and 2-methacryloyloxyethyl phosphorylcholine.

In one embodiment, the polymer of the present invention is prepared by suspension polymerization in an aqueous phase having free radical initiated formulation in the presence of an aqueous phase dispersant selected to provide a biocompatible and hemocompatible outer surface to the formed polymer beads. In some embodiments, the beads are made porous by macroreticular synthesis, using appropriately selected porogens (porogens) and appropriate polymerization time-temperature profiles to form the appropriate pore structure.

In another embodiment, the polymers prepared by suspension polymerization may be rendered biocompatible and hemocompatible by further grafting of biocompatible and hemocompatible monomers or low molecular weight oligomers. It has been shown that the free radical polymerization process does not consume all of the vinyl groups of the DVB introduced for copolymerization. On average, about 30% of DVB material cannot act as a cross-linking bridge and remains participating in the network through only one of the two vinyl groups. Thus, the presence of relatively high levels of pendant vinyl groups is a characteristic of the adsorbent. It is contemplated that these pendant vinyl groups are preferably exposed to the surface of the polymer beads and, if present, their macropores should be amenable to chemical modification. Chemical modification of the surface of DVB copolymers relies on chemical reaction of the surface exposed pendant vinyl groups and is intended to convert these groups into more hydrophilic functional groups. This conversion to the initial hydrophobic adsorbent material by free radical grafting of monomers and/or cross-linkers or low molecular weight oligomers provides hemocompatibility properties.

In another embodiment, the free radical polymerization initiator is first added to the dispersed organic phase, rather than the aqueous dispersion medium typical of suspension polymerization. During polymerization, many growing polymer chains with their chain-end radicals appear at the phase interface and can initiate polymerization in the dispersion medium. In addition, free radical initiators (such as benzoyl peroxide) generate free radicals relatively slowly. Even after several hours of polymerization, the initiator is only partially consumed during bead formation. The initiator readily migrates to the bead surface and activates the surface exposed pendant vinyl groups of the divinylbenzene portion of the bead, thereby initiating graft polymerization of additional monomers added after the reaction has proceeded for a period of time. Thus, free radical grafting can occur during the conversion of the monomer droplets into polymer beads, thereby introducing biocompatible or hemocompatible monomers and/or crosslinkers or low molecular weight oligomers as surface coatings.

The blood perfusion and perfusion device consists of a packed bed of polymer beads in a flow-through container equipped with a retaining screen (retainer screen) at both the outlet and inlet ends to retain the bed of beads within the container, or with a subsequent retaining screen to collect the beads after mixing. Blood perfusion and perfusion operations are performed by passing whole blood, plasma or physiological fluids through a packed bed of beads. During perfusion through the bed of beads, toxic molecules are retained by adsorption, tortuous pathways and/or pore capture, while the remaining fluid and intact cellular components pass through with substantially unchanged concentrations.

In other embodiments, an in-line filter comprises a packed bed of polymer beads in a flow-through vessel equipped with retaining screens at both the outlet end and the inlet end to retain the bed within the vessel. The biological fluid passes from the reservoir bag once through the packed bead bed by gravity, during which the toxic molecules are retained by adsorption, tortuous paths and/or pore capture, while the remaining fluid and intact cellular components pass through with substantially unchanged concentration.

Certain polymers useful in the present invention (as such or after further modification) are macroporous polymers prepared from polymerizable monomers of styrene, divinylbenzene, ethylvinylbenzene and acrylate and methacrylate monomers, such as those listed below by the manufacturer. Rohm and Haas Company (Rohm and Haas Company) (now part of the Dow Chemical Company): macroporous polymeric sorbents, e.g. Amberlite^TM XAD-1、Amberlite^TMXAD-2、Amberlite^TM XAD-4、Amberlite^TM XAD-7、Amberlite^TM XAD-7HP、Amberlite^TM XAD-8、Amberlite^TM XAD-16、Amberlite^TM XAD-16HP、Amberlite^TM XAD-18、Amberlite^TM XAD-200、Amberlite^TM XAD-1180、Amherlite^TM XAD-2000、Amberlite^TM XAD-2005、Amherlite^TM XAD-2010、Amberlite^TMXAD-761 and Amberlite^TMXE-305, and chromatographic grade sorbents, e.g. Amberchrom^TMCG 71，s，m，c、Amberchrom^TM CG 161，s，m，c、Amberchrom^TMCG 300, s, m, c and Amberchrom^TMCG 1000, s, m, c. Dow chemical company: dowex^TMOptipore^TM L-493、Dowex^TM Optipore^TMV-493、Dowex^TMOptipore^TMV-502、Dowex^TM Optipore^TM L-285、Dowex^TM Optipore^TML-323 and Dowex^TMOptipore^TMAnd V-503. Lanxess (Lanxess) (Bayer and Sybron as predecessor): lewatit ^TMVPOC 1064 MD PH、Lewatit^TM VPOC 1163、Lewatit^TM OC EP 63、Lewatit^TMS 6328A、Lewatit^TMOC 1066 and Lewati ^TM60/150 MIBK. Mitsubishi Chemical Corporation (Mitsubishi Chemical Corporation): diaion^TMHP 10、Diaion^TM HP 20、Diaion^TM HP 21、Diaion^TM HP 30、Diaion^TM HP 40、Diaion^TM HP 50、Diaion^TMSP70、Diaion^TM SP 205、Diaion^TM SP 206、Diaion^TM SP 207、Diaion^TM SP 700、Diaion^TM SP 800、Diaion^TM SP 825、Diaion^TMSP 850、Diaion^TM SP 875、Diaion^TM HP 1MG、Diaion^TM HP 2MG、Diaion^TM CHp 55A、Diaion^TM CHP55Y、Diaion^TM CHP 20A、Diaion^TM CHP 20Y、Diaion^TM CHP 2MGY、Diaion^TM CHP 20P、Diaion^TM HP 20SS、Diaion^TM SP 20SS、Diaion^TMSP 207 SS. Blanc corporation (Purolite Company): purosorb^TMAP 250 and Purosorb^TMAP 400, and Kaneka corp.

Other certain polymers useful in the present invention (as such or after further modification) are cellulosic porous materials. Such modifications may include the addition of lipophilic substrates comprising aryl or alkyl groups, as well as by free radicals or S_NType 2 chemically added polyols or zwitterionic substrates.

A variety of proteins can be adsorbed by the compositions of the present disclosure. Some of these proteins and their molecular weights are shown in the table below.

The following examples are intended to be illustrative and not limiting.

Example 1: synthesis of base sorbents CY14175 and CY15077

The reactor is provided with: a 4-neck glass lid was secured to a 3L jacketed cylindrical glass reaction vessel using a stainless steel flange clamp and a PFTE gasket. The lid was fitted with a PFTE stirrer bearing, an RTD adapter and a water-cooled reflux condenser. A stainless steel stirring shaft with five 60 ° stirrers was fitted through the stirrer bearing and inserted into the digital overhead stirrer. The RTDs were fitted through respective adapters and connected to a PolyStat circulation heating and cooling unit. The inlet and outlet of the reaction vessel jacket were connected to appropriate ports on the polystate using compatible tubing. The unused ports in the lid were used to charge the reactor and were plugged at all other times.

Polymerization: the aqueous and organic phase compositions are shown in tables I and II below, respectively. Ultrapure water was divided into approximately equal portions in two separate erlenmeyer flasks, each containing a PFTE coated magnetic stir bar. Poly (vinyl alcohol) (PVA) with a degree of hydrolysis of 85.0 to 89.0 mol% and a viscosity of 23.0 to 27.0cP in a 4% aqueous solution at 20 ℃ is dispersed in water in a first bottle and heated to 80 ℃ on a hot plate with stirring. The salts (see table 1, MSP, DSP, TSP and sodium nitrite) were dispersed in a second vial of water and heated to 80 ℃ on a hot plate with stirring. Circulation of heat transfer fluid from the polyst through the reaction vessel jacket was started and the fluid temperature was heated to 60 ℃. Once the PVA and salt were dissolved, the two solutions were added one at a time to the reactor using a glass funnel. The digital overhead stirrer was powered on and the rpm was set to a value to form the appropriate droplet size after addition of the organic phase. The temperature of the aqueous phase in the kettle was set to 70 ℃. The organic phase was prepared by adding Benzoyl Peroxide (BPO) to Divinylbenzene (DVB) in a 2L erlenmeyer flask and vortexing until completely dissolved. 2, 2, 4-trimethylpentane and toluene were added to the bottle and vortexed until well mixed. Once the temperature of the aqueous phase in the reactor reached 70 ℃, the organic phase was charged to the reactor using a narrow-neck glass funnel. The temperature of the reaction volume decreased after the addition of the organics. The temperature program for polystate was started, the reaction volume was heated from 60 ℃ to 77 ℃ over 30 minutes, from 77 ℃ to 80 ℃ over 30 minutes, held at a temperature of 80 ℃ for 960 minutes, and cooled to 20 ℃ over 60 minutes.

Post-treatment (work-up): the reaction volume level in the reactor is marked. The overhead stirrer was stopped, the remaining liquid was siphoned out of the reactor, and the reactor was filled to the mark with ultra pure water at room temperature. The overhead stirrer stirring was restarted and the slurry was heated to 70 ℃ as soon as possible. After 30 minutes, the stirring was stopped and the remaining liquid was siphoned off. The polymer beads were washed five times in this manner. During the final wash, the slurry temperature was cooled to room temperature. After the final water wash, the polymer beads were washed in the same manner with 99% Isopropanol (IPA). 99% IPA was siphoned off and replaced with 70% IPA, after which the slurry was transferred to a clean 4L glass container. Unless otherwise stated, the polymer was steam stripped as needed in stainless steel tubing for 8 hours, rewetted in 70% IPA, transferred into DI water, sieved to obtain only bead fractions of 300 to 600 μm in diameter, and dried at 100 ℃ until no further weight loss was observed upon drying.

Cumulative pore volume data for polymers CY14175 and CY15077, measured by nitrogen desorption isotherms and mercury intrusion porosimetry, respectively, are shown in tables III and IV, respectively, below.

Example 2: polymer modification CY15129

Epoxidation: 50.8g of dry base polymer CY14175 were added to a 1L jacketed glass reactor equipped with a Teflon coated stirrer and RTD probe. 300mL of acetic anhydride (99%) was added to the reactor containing the dried base polymer. The mixture was cooled to 5 ℃ with continuous stirring at 100 RPM. 30mL of hydrogen peroxide solution (30% aqueous solution) was added over a period of 30 minutes. The reaction temperature was maintained at 10 ℃ to 15 ℃ for 24 hours with stirring at 100 RPM.

And (3) post-treatment: the reaction mixture was washed with acetic acid and then with DI water until the pH of the reaction supernatant was neutral. The polymer was then dried at 80 ℃ until no further loss on drying was observed. The yield of dry polymer was 61.6 g.

The epoxidation procedure described above should not be scaled up to a reaction volume of greater than 1L. Diacetyl peroxide can be formed if the desired intermediate compound, peracetic acid, is combined with an excess of acetic anhydride. Diacetyl peroxide is known to be an explosive sensitive to shock (http:// cen. acs. org/articules/89/i 2/Chemical-Safety-Synthesis-procedure. html). It is therefore emphasized that alternative epoxidation processes may be used as far as possible.

Opening the ring: 20.0g of dry epoxide-functional polymer was added to a 500mL jacketed glass reactor equipped with a Teflon coated stirrer and RTD probe. 70mL of 70% isopropyl alcohol (IPA) was added to the reactor and the mixture was stirred at 100 RPM. 70mL of 1M NaOH (aq) was added slowly. The reaction temperature was raised to 70 ℃ and maintained at 70 ℃ for 24 hours with stirring at 100 RPM.

And (3) post-treatment: the reaction was cooled to room temperature and washed with DI water until the pH of the reaction supernatant was neutral. The result of this process is a poly (styrene-co-divinylbenzene) resin functionalized with 1, 2-diol groups.

The cumulative pore volume data for polymer CY15129 as measured by nitrogen desorption isotherm is shown in table V below. Table VI shows the atomic concentration of polymer CY15129 as measured by XPS. The log differential pore volume plot of polymer CY15129 is shown in figure 1 below.

Thrombogenicity was measured by the uttt assay, where the material was compared to a negative control (plasma only), a positive control (glass beads) and reference beads to determine the extent of contact activation activity. In the uppt assay, the% change in clot formation over time compared to the reference material was determined and then grouped according to: < 25% activator, 25-49% moderate activator, 50-74% mild activator, 75-100% minimal activator, and > 100% non-activator of the intrinsic coagulation pathway. Polymer CY15129 was 97% and is the minimum activator.

Example 3: polymer modification CY15154

20.05g of dried base polymer CY15077 were added to a 500mL jacketed glass reactor equipped with a Teflon coated stirrer and RTD probe. The dried polymer was re-wetted into DI water and 100mL of slurry was prepared in the reactor. 9.00g of zwitterionic neutral methacrylate monomer [ (2-methacryloyloxy) ethyl ] -dimethyl-3- (sulfopropyl) ammonium hydroxide and 1.1g of ammonium persulfate were dissolved in 100ml DI water and the solution was added to the reactor containing the base polymer slurry. The mixture was heated to 75 ℃ and kept at 75 ℃ for 24 hours with stirring at 100 RPM.

And (3) post-treatment: the reaction mixture was cooled to room temperature and washed with DI water until the pH of the reaction supernatant was neutral. The result of this process is a poly (styrene-co-divinylbenzene) resin having sulfobetaine functionality.

The cumulative pore volume data for polymer CY15154 measured by mercury intrusion porosimetry are shown in table VII below. Table VIII shows the atomic concentration of polymer CY15154 as measured by XPS. The log differential pore volume plot for polymer CY15154 is shown in figure 2 below.

Thrombogenicity was measured by the uPTT assay, in which the material was compared to a negative control (plasma only), a positive control (glass beads) and a reference bead to determine the extent of contact activation activity. In the uppt assay, the% change in clot formation over time compared to the reference material was determined and then grouped according to: less than 25% activator, 25-49% moderate activator, 50-74% mild activator, 75-100% minimal activator, and > 100% non-activator of the intrinsic coagulation pathway. Polymer CY15154 was 89%, the minimum activator.

Example 4: polymer modification CY16029

200mL of base polymer CY14175, wetted in DI water, were added to a 1000mL jacketed glass reactor equipped with a Teflon coated stirrer and RTD probe. Excess water was removed from the reactor using a vacuum pump and filter tubes. 500mL of 1.0M sodium hydroxide was added to the reactor. The mixture was heated to 50 ℃ and kept at 50 ℃ for 24 hours with stirring at 100 RPM.

And (3) post-treatment: the reaction mixture was cooled to room temperature and washed with DI water until the pH of the reaction supernatant was neutral. The result of this process is a poly (styrene-co-divinylbenzene) resin having diol functional groups.

Example 5: base sorbent Synthesis CY15186

The reactor is provided with: a 4-neck glass lid was secured to a 1L jacketed cylindrical glass reaction vessel using a stainless steel flange clamp and a PFTE gasket. The lid was fitted with a PFTE stirrer bearing, an RTD adapter and a water cooled reflux condenser. A stainless steel stirring shaft with four 60 ° stirrers was fitted through the stirrer bearings and inserted into the digital overhead stirrer. The RTDs were mounted through respective adapters and connected to the PolyStat circulation heating and cooling unit. The inlet and outlet of the reaction vessel jacket were connected to appropriate ports on the polystate using compatible tubing. The unused ports in the lid were used to charge the reactor and were plugged at all other times.

Polymerization: the aqueous and organic phase compositions are shown in tables IX and X below, respectively. Ultrapure water was added to the flask containing the PFTE coated magnetic stir bar. Poly (vinyl alcohol) (PVA) with a degree of hydrolysis of 85.0 to 89.0 mol% and a viscosity of 23.0 to 27.0cP in a 4% aqueous solution at 20 ℃ is dispersed in water in a bottle and heated to 80 ℃ on a hot plate with stirring. Circulation of heat transfer fluid from the PolyStat through the reaction vessel jacket was started and the fluid temperature was heated to 60 ℃. Once the PVA was dissolved, the solution was added to the reactor using a glass funnel. The digital overhead stirrer was powered on and the rpm was set to a value to form the appropriate droplet size after addition of the organic phase. The temperature of the aqueous phase in the kettle was set to 70 ℃. The organic phase was prepared by adding Benzoyl Peroxide (BPO) to Divinylbenzene (DVB) and Allyl Glycidyl Ether (AGE) in a 1L erlenmeyer flask and vortexing until completely dissolved. 2, 2, 4-trimethylpentane and toluene were added to the bottle and vortexed to mix well. Once the temperature of the aqueous phase in the reactor reached 70 ℃, the organic phase was charged to the reactor using a narrow-necked glass funnel. The temperature of the reaction volume decreased after the addition of the organic. The temperature program for PolyStat was started, the reaction volume was heated from 60 ℃ to 77 ℃ over 30 minutes, from 77 ℃ to 80 ℃ over 30 minutes, held at a temperature of 80 ℃ for 960 minutes, and cooled to 20 ℃ over 60 minutes.

Table X: organic phase composition

And (3) post-treatment: the reaction volume level in the reactor is marked. The overhead stirrer was stopped, the remaining liquid was siphoned out of the reactor, and the reactor was filled to the mark with ultra pure water at room temperature. Overhead stirrer stirring was restarted and the slurry was heated to 70 ℃ as soon as possible. After 30 minutes, the stirring was stopped and the remaining liquid was siphoned off. The polymer beads were washed five times in this manner. During the final wash, the slurry temperature was cooled to room temperature. After the final water wash, the polymer beads were washed in the same manner with 99% Isopropanol (IPA). 99% IPA was siphoned off and replaced with 70% IPA, after which the slurry was transferred to a clean 2L glass container. Unless otherwise stated, the polymer was steam stripped in stainless steel tubing for 8 hours as needed, rewetted in 70% IPA, transferred to DI water, sieved to obtain only a bead fraction of 300 to 600 μm in diameter, and then dried at 100 ℃ until no further weight loss was observed upon drying.

The cumulative pore volume data for polymer CY15186 as measured by mercury intrusion porosimetry is shown in table XI below.

Example 6: polymer modification CY16000

Opening the ring: 100mL of polymer CY15186, wetted in 70% IPA, was added to a 1L jacketed glass reactor equipped with a Teflon coated stirrer and RTD probe. 300mL of 1M NaOH (aq) was added slowly. The reaction temperature was raised to 80 ℃ and maintained at 80 ℃ for 24 hours with stirring at 100 RPM.

And (3) post-treatment: the reaction was cooled to room temperature and washed with DI water until the pH of the reaction supernatant was neutral. The result of this process is a poly (allyl glycidyl ether-co-divinylbenzene) resin functionalized with 1, 2-diol groups.

The cumulative pore volume data for polymer CY16000, as measured by mercury intrusion porosimetry, is shown in table XII below. Table XIII shows the atomic concentration of polymer CY16000 as measured by XPS. The log differential pore volume plot for polymer CY16000 is shown in figure 3 below.

Thrombogenicity was measured by the uPTT assay, in which the material was compared to a negative control (plasma only), a positive control (glass beads) and a reference bead to determine the extent of contact activation activity. In the uPTT assay, the% change in clot formation over time compared to the reference material was determined and then grouped according to: less than 25% activator, 25-49% moderate activator, 50-74% mild activator, 75-100% minimal activator, and > 100% non-activator of the intrinsic coagulation pathway. Polymer CY16000 was 84%, the minimum activator.

Example 7: synthesis of base sorbent CY16207

The reactor is provided with: a stainless steel flange clamp and PFTE gasket were used to secure a 4-neck glass lid to a 3L jacketed cylindrical glass reaction vessel. The lid was fitted with a PFTE stirrer bearing, an RTD adapter and a water-cooled reflux condenser. A stainless steel stirring shaft with five 60 ° stirrers was fitted through the stirrer bearing and inserted into the digital overhead stirrer. The RTDs were fitted through corresponding adapters and connected to the polystate circulation heating and cooling units. The inlet and outlet of the reaction vessel jacket were connected to appropriate ports on the polystate using compatible tubing. The unused port in the lid was used to charge the reactor and was plugged at all other times.

Polymerization: the aqueous and organic phase compositions are shown in Table XIV and Table XV, respectively. Ultrapure water was divided into approximately equal portions in two separate erlenmeyer flasks, each containing a PFTE coated magnetic stir bar. Poly (vinyl alcohol) (PVA) with a degree of hydrolysis of 85.0 to 89.0 mol% and a viscosity of 23.0 to 27.0cP in a 4% aqueous solution at 20 ℃ is dispersed in water in a first bottle and heated to 80 ℃ on a hot plate with stirring. The salts (see table 1, MSP, DSP, TSP and sodium nitrite) were dispersed in a second vial of water and heated to 80 ℃ on a hot plate with stirring. Circulation of heat transfer fluid from the polyst through the reaction vessel jacket was started and the fluid temperature was heated to 60 ℃. Once the PVA and salt were dissolved, the two solutions were added one at a time to the reactor using a glass funnel. The digital overhead stirrer was powered on and the rpm was set to a value to form the appropriate droplet size after addition of the organic phase. The temperature of the aqueous phase in the kettle was set to 60 ℃. The organic phase was prepared by adding Benzoyl Peroxide (BPO) to Divinylbenzene (DVB) and Vinyl Acetate (VA) in a 2L erlenmeyer flask and vortexing until completely dissolved. 2, 2, 4-trimethylpentane and toluene were added to the bottle and vortexed until well mixed. Once the temperature of the aqueous phase in the reactor reached 60 ℃, the organic phase was charged to the reactor using a narrow-necked glass funnel. The temperature of the reaction volume decreased after the addition of the organics. The temperature program for PolyStat was started, the reaction volume was heated from 50 ℃ to 67 ℃ over 30 minutes, from 67 ℃ to 70 ℃ over 30 minutes, held at a temperature of 70 ℃ for 960 minutes, and cooled to 20 ℃ over 60 minutes.

And (3) post-treatment: the reaction volume level in the reactor is marked. The overhead stirrer was stopped, the remaining liquid was siphoned out of the reactor, and the reactor was filled to the mark with ultra pure water at room temperature. Overhead stirrer stirring was restarted and the slurry was heated to 70 ℃ as soon as possible. After 30 minutes, the stirring was stopped and the remaining liquid was siphoned off. The polymer beads were washed five times in this manner. During the final wash, the slurry temperature was cooled to room temperature. After the final water wash, the polymer beads were washed in the same manner with 99% Isopropanol (IPA). 99% IPA was siphoned off and replaced with 70% IPA, after which the slurry was transferred to a clean 4L glass container. Unless otherwise stated, the polymer was steam stripped in stainless steel tubing for 8 hours as needed, rewetted in 70% IPA, transferred into DI water, sieved to obtain only a bead fraction of 300 to 600 μm in diameter, and then stored in 70% IPA.

Example 8: polymer modification CY16083

Opening the ring: 100mL of polymer CY16207 wetted in 70% IPA was added to a 1L jacketed glass reactor equipped with Teflon^TMCoated stirrer and RTD probe. 300mL of 1M NaOH (aq) was added slowly. The reaction temperature was raised to 50 ℃ and held at 50 ℃ for 24 hours with stirring at 100 RPM.

And (3) post-treatment: the reaction was cooled to room temperature and washed with DI water until the pH of the reaction supernatant was neutral. The result of this process is a poly (vinyl acetate-co-divinylbenzene) resin functionalized with diol groups.

The cumulative pore volume data of polymer CY16083, measured by mercury porosimetry, are shown in table XVI below. The log differential pore volume plot for polymer CY16083 is shown in figure 4 below.

Example 9: pore structure overview and Classification

Pore structure (including pore size, pore size distribution, and surface properties) is very important to the adsorption characteristics of porous materials. IUPAC has divided pores into micro pores (micropore), meso pores (mesopore) and macro pores (macropore); this is a term widely used in the fields of adsorption, catalysis, and the like.

The width of the micropores is less than 2nm

。

The width of the mesopores is 2 to 50nm

。

The width of macropores is more than 50nm

。

Under the definition of IUPAC, the pore size (or pore diameter) is the distance between two opposing walls of a pore, and thus refers to the diameter of a cylindrical pore, or the width of a slit-shaped pore. In addition to the IUPAC classification, the term transport pore (pore size larger than)

) Has been used in the field of activated carbon adsorption. For purposes of description in this application, the term "large transport pore" refers to a pore having a diameter greater than

The pore of (b), a subclass of macropores; the term "volumetric hole" means a diameter greater than

A pore capable of adsorbing small and medium sized biomolecules and proteins (to 50 kDa); the term "effective aperture" refers to a diameter of

The pores of (a), which are a subset of mesopores, have been shown to be the most efficient pores for adsorption of small and medium-sized proteins.

While mesoporous pores are useful adsorption sites, the macropores provide a transfer path for the adsorbate to reach the internal adsorption sites. Large transport pores provide a more efficient transport pathway, which is particularly important for large molecules, such as large proteins, endotoxins, and other large toxin molecules. The present invention discloses techniques to generate a wide pore size distribution including large transport pores, conventional macropores, mesopores, and micropores to supplement special needs in adsorption applications. Table XVII summarizes the pore size distributions of the polymer examples disclosed in this application, including IUPAC classification and size fractions important for protein and biomolecule adsorption.

Example 10: endotoxin removal from plasma in a recirculation model

20mL of heat-inactivated human citrated plasma was spiked with 3EU/mL endotoxin purchased from Associates of cape Cod, East Falmouth, MA and then spiked into the plasma reservoir. The plasma with endotoxin was mixed on a stir plate for 15 minutes and recirculated through a 1.5mL polymer column at a flow rate of 2.5 mL/min. Samples were collected from the reservoir using a sterile pipette tip and diluted 1: 20 in endotoxin-free water. All diluted samples were tested in a Pierce LAL autoxin Assay from Life Technologies, corp. Data for the removal of endotoxin from plasma in a dynamic recirculation model using modified polymers CY15129, CY15154, CY16000, and CY16029 are shown below in figure 5. Figure 6 shows endotoxin removal data for polymer CY15154 and its unmodified precursor polymer CY 15077.

Example 11: cytokine removal from whole bovine blood in a recirculation model

The purified protein was added to 300mL of 3.8% citrated whole bovine blood (Lampire Biologicals) at the expected clinical concentration and recirculated through a 20mL polymer-filled device at a flow rate of 140mL/min for 5 hours. Protein and initial concentrations were: IL-63000pg/mL and TNF- α 800 pg/mL. Plasma was analyzed by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions (R & D Systems). Data for cytokine removal from whole blood using polymer CY15129 in a dynamic recirculation model is shown below in figure 7.

Claims (48)

1. A biocompatible polymer system comprising at least one polymer comprising a polyol or zwitterionic functional group; the polymer system is capable of adsorbing endotoxins; wherein adsorption of said endotoxin occurs with blood perfusion or by enteral or rectal administration of said polymer, and wherein said polymer comprises a solid support having a biocompatible hydrogel coating comprising polyethylethylaminomethacrylate, dimethylaminoethylmethacrylate, polyhydroxyethylacrylate, polyhydroxyethylmethacrylate, polyhydroxypropylacrylate, polyhydroxypropylmethacrylate, poly-N-vinylpyrrolidone, polyvinyl alcohol, polyacrylate, polymethacrylate, or mixtures thereof.

2. The biocompatible polymer system of claim 1 wherein the polymer system is further capable of adsorbing a plurality of toxins and inflammatory mediators.

3. The biocompatible polymer system of claim 2 wherein the toxins and inflammatory mediators have a molecular weight of less than 0.5kDa to 1,000 kDa.

4. The biocompatible polymer system of claim 2 wherein the toxins and inflammatory mediators have a molecular weight of less than 0.5kDa to 60 kDa.

5. The biocompatible polymer system of claim 2 wherein the toxins and inflammatory mediators comprise one or more of: cytokines, pathogen-associated molecular pattern molecules, damage-associated molecular pattern molecules, superantigens, interferons, enzymes, peptides, soluble CD40 ligands, bioactive lipids, cell-free hemoglobin, cell-free myoglobin, glycoproteins, prions, toxins, drugs, vasoactive substances, foreign antigens, and antibodies.

6. The biocompatible polymer system of claim 2 wherein the toxins and inflammatory mediators comprise one or more of: monokines, chemokines, proteases, bradykinin, oxidized lipids, growth factors, and bacterial and viral toxins.

7. The biocompatible polymer system of claim 1 wherein the polymer system is further capable of adsorbing one or more of: gram-negative bacteria, gram-negative bacterial fragments and gram-negative bacterial components.

8. The biocompatible polymer system of claim 1 wherein the polymer system is further capable of adsorbing one or more of: gram positive bacteria, gram positive bacterial fragments and gram positive bacterial components.

9. The biocompatible polymer system of claim 1 wherein the polymer system is further capable of adsorbing one or more of: lipopolysaccharides and lipoteichoic acids.

10. The biocompatible polymer system of claim 1 wherein the polymer is prepared using suspension polymerization, emulsion polymerization, bulk polymerization, or precipitation polymerization.

11. The biocompatible polymer system of claim 1 wherein said polymer is prepared by modification of a cellulosic polymer, wherein said modification comprises addition of a lipophilic substrate comprising an aryl or alkyl group and a polyol or zwitterionic substrate added by free radical or SN2 type chemistry.

12. The biocompatible polymer system of claim 1 wherein the polymer system is in the form of a solid support including but not limited to beads, fibers, monolithic columns, or membranes.

13. The biocompatible polymer system of claim 12 wherein the solid support comprises but is not limited to a thin film or semi-permeable membrane.

14. The biocompatible polymer system of claim 12 wherein the solid support has a biocompatible hydrogel coating.

15. The biocompatible polymer system of claim 1 wherein the polymer comprises a plurality of pores and the polymer pore structure is in

To is that

The total volume of pore sizes in the range is greater than 0.1cc/g and less than 5.0cc/g dry polymer.

16. The biocompatible polymer system of claim 1 wherein the polymer is non-porous.

17. The biocompatible polymer system of claim 1 wherein the polymer is a hypercrosslinked polymer.

18. The biocompatible polymer system of claim 1 wherein the polymer is hemocompatible.

19. The biocompatible polymer system of claim 1 wherein the agent for imparting biocompatibility is (i) heparin or (ii) a heparin mimetic polymer.

20. The biocompatible polymer system of claim 1 wherein the polymer is formed and subsequently modified to be biocompatible.

21. The biocompatible polymer system of claim 20 wherein the agent for imparting biocompatibility is (i) heparin or (ii) a heparin mimetic polymer.

22. A device for removing endotoxins from physiological fluids comprising the biocompatible polymer system of any one of claims 1-21.

23. The device of claim 22, wherein the device also removes a plurality of toxins and inflammatory mediators.

24. The device of claim 23, wherein the toxins and inflammatory mediators have a molecular weight of less than 0.5kDa to 1,000 kDa.

25. The device of claim 23, wherein the toxins and inflammatory mediators have a molecular weight of less than 0.5kDa to 60 kDa.

26. The device of claim 23, wherein the toxin and inflammatory mediator comprise one or more of: cytokines, pathogen-associated molecular pattern molecules, damage-associated molecular pattern molecules, superantigens, interferons, enzymes, peptides, soluble CD40 ligand, bioactive lipids, cell-free hemoglobin, cell-free myoglobin, glycoproteins, prions, toxins, drugs, vasoactive substances, foreign antigens, and antibodies.

27. The device of claim 23, wherein the toxin and inflammatory mediator comprise one or more of: monokines, chemokines, proteases, bradykinin, oxidized lipids, growth factors, and bacterial and viral toxins.

28. The apparatus of claim 22, wherein the apparatus further removes one or more of: gram-negative bacteria, gram-negative bacterial fragments and gram-negative bacterial components.

29. The apparatus of claim 22, wherein the apparatus further removes one or more of: gram positive bacteria, gram positive bacterial fragments and gram positive bacterial components.

30. The apparatus of claim 22, wherein the apparatus further removes one or more of: lipopolysaccharide and lipoteichoic acid.

31. A device for removing endotoxins from non-physiological fluids comprising the biocompatible polymer system of any one of claims 1-21.

32. The device of claim 31, wherein the device also removes a plurality of toxins and inflammatory mediators.

33. The device of claim 32, wherein the toxins and inflammatory mediators have a molecular weight of less than 0.5kDa to 1,000 kDa.

34. The device of claim 32, wherein the toxins and inflammatory mediators have a molecular weight of less than 0.5kDa to 60 kDa.

35. The device of claim 32, wherein the toxin and inflammatory mediator comprise one or more of: cytokines, pathogen-associated molecular pattern molecules, damage-associated molecular pattern molecules, superantigens, interferons, enzymes, peptides, soluble CD40 ligand, bioactive lipids, cell-free hemoglobin, cell-free myoglobin, glycoproteins, prions, toxins, drugs, vasoactive substances, foreign antigens, and antibodies.

36. The device of claim 32, wherein the toxin and inflammatory mediator comprise one or more of: monokines, chemokines, proteases, bradykinin, oxidized lipids, growth factors, and bacterial and viral toxins.

37. The apparatus of claim 31, wherein the apparatus further removes one or more of: gram-negative bacteria, gram-negative bacterial fragments and gram-negative bacterial components.

38. The apparatus of claim 31, wherein the apparatus further removes one or more of: gram positive bacteria, gram positive bacterial fragments and gram positive bacterial components.

39. The apparatus of claim 31, wherein the apparatus further removes one or more of: lipopolysaccharide and lipoteichoic acid.

40. The biocompatible polymer system of any one of claims 1-21 in a device adapted to retain said polymer and be incorporated into an extracorporeal circuit.

41. A perfusion method comprising a single pass of a physiological fluid or multiple passes through a device comprising the biocompatible polymer system of any one of claims 1-21 with the aid of a suitable extracorporeal circuit.

42. The biocompatible polymer system of any one of claims 1-21 contained in a container adapted to retain said polymer and for infusion of a blood product comprising whole blood, packed red cells, platelets, albumin, plasma, or any combination thereof.

43. The biocompatible polymer system of any one of claims 1-21 which removes endotoxins from blood products including whole blood, plasma or serum or from other physiological fluids.

44. The biocompatible polymer system of any one of claims 1-21 wherein said polymer is administered enterally or rectally.

45. A polymer system comprising at least one polymer comprising a polyol or zwitterionic functional group; the polymer system is capable of adsorbing endotoxins; wherein adsorption of said endotoxin occurs with blood perfusion or by enteral or rectal administration of said polymer, and wherein said polymer comprises a solid support having a biocompatible hydrogel coating comprising polyethylethylaminomethacrylate, dimethylaminoethylmethacrylate, polyhydroxyethylacrylate, polyhydroxyethylmethacrylate, polyhydroxypropylacrylate, polyhydroxypropylmethacrylate, poly-N-vinylpyrrolidone, polyvinyl alcohol, polyacrylate, polymethacrylate, or mixtures thereof.

46. The polymer system of claim 45, wherein the polymer system is further capable of adsorbing one or more of: a plurality of toxins, gram-negative bacteria, gram-negative bacterial fragments, gram-negative bacterial components, gram-positive bacteria, gram-positive bacterial fragments, and gram-positive bacterial components.

47. The polymer system of claim 46, wherein the polymer system is further capable of adsorbing one or more of: lipopolysaccharides and lipoteichoic acids.

48. The polymer system of claim 46, wherein the toxin has a molecular weight of less than 0.5kDa to 1,000 kDa.

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